ORIENTAL JOURNAL OF CHEMISTRY

An International Open Free Access, Peer Reviewed Research Journal

www.orientjchem.org

ISSN: 0970-020 X
CODEN: OJCHEG
2015, Vol. 31, No. (2):
Pg. 1175-1179

One-pot Three-component Synthesis

of Spirooxindoles Catalyzed by Nano Ag/kaolin
BAHAREH SADEGHI1, ZAHRA LASEMI2 and RAZIEH AZIMI3
1

Department of Chemistry, Yazd Branch, Islamic Azad University, P.O. Box 89195-155, Yazd, Iran.
2
Department of Chemistry, Firoozkooh Branch, Islamic Azad University, Firoozkooh, Iran.
3
Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, Iran.
*Corresponding author E-mail: sadeghi@iauyazd.ac.ir
http://dx.doi.org/10.13005/ojc/310272
(Received: February 04, 2015; Accepted: March 18, 2015)
ABSTRACT
Nano Ag/kaolin has been used as an effective heterogeneous catalyst for one-pot synthesis
of spiro[4H-pyran-3,3'-oxindoles] via reaction of isatin derivatives, malononitrile and cyclic 1,3diketones under mild reaction conditions in excellent yields.

Key words: Spirooxindoles, Heterogeneous catalyst,

Cyclic 1,3-diketone, Nano Ag/kaolin, Malononitrile.

INTRODUCTION
Multicomponent reactions forming
heterocyclic compounds are powerful tools in the
drug discovery process as they can offer expedient
synthesis of libraries of drug like compounds in
single operation1.
Spirooxindoles occupy an important place
in the area of heterocyclic chemistry because they
are frequently found in numerous natural and
synthetic products along with useful
biopharmaceutical, physiopharmaceutical, and
pharmaceutical activities2-7.

In recent years, several improved protocols

for the synthesis of spirooxindoles with fused
chromenes have been reported by modification of
three-component condensation of isatin derivatives,
activated methylene reagents, and 1,3-dicarbonyl
compounds using various catalysts such as
triethylbenzyl ammonium chloride (TEBA)8, InCl39,
NEt310, electrogenerated base (NaBr/ROH)11, cyclodextrin12, [BMIm]BF413, L-proline14 ,MgO15,
surfactant
metal
carboxylates 16 ,
ethylenediaminediacetate17, CarbonSO3H18, ZnS
NPs19. Although all of these methods are effective,
but some of them have drawbacks such as, harsh
reaction conditions 9 , long reaction times 8,12 ,
technical intricacy11, use of expensive13, unsafe10,

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SADEGHI et al., Orient. J. Chem., Vol. 31(2), 1175-1179 (2015)

and unreusable catalysts8,10,16,17. Therefore, the

development of a new and simple synthetic method
for the preparation of spirooxindole derivatives has
become an interesting challenge.
During the recent years, the use of
heterogeneous
catalysts
has
received
considerable importance in organic synthesis
because of their environmental, economical and
industrial aspects20. Metal colloids, mineral clays
and supported reagents on silica gel, alumina and
other solid supports are some common examples
of heterogeneous catalysts that have extensive
applications in organic transformations. These

catalysts have attracted a great deal of attention due

to their ease of handling, enhanced reaction rates,
greater selectivity and simple work up in most cases21.
As a part of our ongoing efforts towards
the development of new procedure for the synthesis
of spirooxindoles through multi component reaction,
we have discovered an effcient and environmentally
friendly procedure for the synthesis of spiro[4Hpyran-3,3'-oxindole] derivatives. We report herein,
for the first time, a simple, mild and expeditious
synthesis of spirooxindoles in high yields using
nano Ag/kaolin as a catalyst in ethanol (Scheme 1).
R"

R'
CN
CN

R
O

Nano Ag/kaolin

O
R'

N
H

R"

1a-d
O

3a-b

O
NH2

EtOH, ref
N
H

O CN

4a-h

R'=R"=H
3a
R'=R"=Me 3b

Scheme 1: Synthesis of spirooxindoles by the reaction of isatin derivatives,

with malononitrile and cyclic 1,3-diketones catalyzed by nano Ag/kaolin
EXPERIMENTAL
The chemical materials used in this work
were obtained from Merck and Aldrich and used
without purification. 1H NMR spectra was recorded
on a Bruker DRX-400 AVANCE spectrometer at 400
MHz. The powder X-ray diffraction studies were
made on Philips PW3719 X-ray diffractometer by
using Cu-K5 radiation. Transmission electron
microscopy (TEM) images were obtained using a
Phlips CM10 microscope operated at 200 kV. Melting
points were determined on a thermo scientific
IA9200 and are uncorrected.
General procedure for the synthesis of
spirochromenes (4)
A mixture of substituted isatins (1 mmol),
cyclic 1,3-diketone (1 mmol), malononitrile (1 mmol)
and nano Ag/kaolin (0.085 g, 7 mol%) in EtOH

(10mL) was stirred at reflux temperature. Upon

completion instead of compilation, monitored by TLC
(n-hexane/ethyl acetate: 2/1), the reaction mixture was
allowed to cool to room temperature. The catalyst was
separated by filtration of this solution. The solution was
concentrated under vacuum to afford the product,
which was purified by recrystallization in the ethanol.
All the products were identified by comparing of melting
point and 1H NMR spectra with those of authentic
samples reported in the literature.
2- Amino -5' - Nitro -2 ' , 5- Ioxo -5 , 6 , 7 , 8 Tetrahydrospiro[Chrom-ene-4,3'-Indoline]-3Carbonitrile (4c).
m.p. 283-285 C; 1 H NMR (400 MHz,
DMSO-d6) : 1.79 -2.02 (m, 2H, CH2), 2.22-2.26 (m,
2H, CH2), 2.62-2.69 (m, 2H, CH2), 7.03 (d, J=8.6
Hz, 1H), 7.40 (brs, 2H, NH2), 7.87 (s, 1H, ArH), 8.13
(d, J= 6.22 Hz, 1H, ArH), 11.17 (s, 1H, NH).

SADEGHI et al., Orient. J. Chem., Vol. 31(2), 1175-1179 (2015)

1177

7.06 (s, 1H, ArH), 7.16 (d, J=8.2 Hz, 1H, ArH), 7.27
(brs, 2H, NH2), 10.65 (s, 1H, NH).

2-Amino-5'-chloro-2',5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3'-indoline]-3-carbonitrile (4d)
m.p. 293294 C (dec); 1H NMR (400 MHz,
DMSO-d6) : 1.89-2.00 (m, 2H, CH2), 2.21 (t, J = 6.8
Hz, 2H, CH2), 2.64 (t, J = 6.4 Hz, 2H, CH2), 6.81 (d,
J = 8.4 Hz, 1H, ArH), 7.18 (d, J = 2.0 Hz, 1H, ArH),
7.24 (d, J = 8.0 Hz, 1H, ArH), 7.31(brs, 2H, NH2),
10.57 (s, 1H, NH).

RESULTS AND DISCUSSION

2-Amino-1',2',5,6,7,8-hexahydro-5',7,7-trimethyl2',5-dioxospiro[4H-1-benzopyran-4,3'[3H]indole]-3-carbonitrile (4f)
m.p. 275-277 C; 1H NMR (400 MHz,
DMSO-d6) : 0.99 (s, CH3 ), 1.03 (s, CH3), 2.11-2.15
(m, CH2), 2.19 (s, CH3), 2.50-2.53 (m, CH2), 6.68 (d,
J=7.6, 1H, ArH), 6.75 (s, 1H, ArH), 6.90 (d, J=10.4,
1H, ArH), 7.14 (br. s, NH2), 10.26 (s, NH).

Initially, nano Ag/kaolin was prepared by

the method described in literature.22 In continution
of our investigations of the application of solid acids
in organic synthesis23-25 we bought a mild and
convenient method for the synthesis of spiro[4Hpyran-3,3'-oxindoles]. Our investigation began with
the evaluation of nano Ag/kaolin as a catalyst in
the reaction of 5-bromoisatin (1 mmol),
malononitrile (1 mmol), and 1,3-cyclohexadione (1
mmol) in EtOH. The use of 20 mol% of nano Ag/
kaolin in this condition afforded a 94% yield (Table
1, entry 5) of the desired product.

2-Amino-5'-Chloro-8,8-Dimethyl-2',5-Dioxo5,6,7,8-Tetrahydrospiro[Chromene-4,3'-Indoline]3-Carbonitrile (4h)
m.p. 288-289 C; 1 HNMR (400 MHz,
DMSO-d6) : 1.01 (s, 6H, CH3), 2.11(s, 2H, CH2),
2.60-2.43 (m, 2H, CH2), 6.79 (d, J=8.1Hz, 1H, ArH),

At the same time a decline in yield was

observed by using kaolin as catalyst (Table 1, entry
9). In the absence of catalyst, the reaction proceeded
sluggishly (Table 1, entry 10). The influence of other
solvents was also examined. The above experiment
was performed in various solvents including

Table 1: Optimization of reaction conditions for the synthesis of 4a

CN
CN

Br
O

Catalyst

NH2

Condition

N
H

1a

Br

N
H
O

CN

4a

3a

Entry

Catalyst

Solvent

Temperature C

Yield %b

1
2
3
4
5
6
7
8
9
10

Nano Ag/kaolin
Nano Ag/kaolin
Nano Ag/kaolin
Nano Ag/kaolin
Nano Ag/kaolin
Nano Ag/kaolin 2nd run
Nano Ag/kaolin 3rd run
Nano Ag/kaolin
Kaolin
-

THFa
MeCNa
H2 Oa
CH 2Cl2a
EtOHa
EtOHa
EtOHa
EtOH
EtOHa
EtOHa

Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
25
Reflux
Reflux

15
10
45
30
94
90
87
50
67
-

60 min at reflux temperature in 10 mL solvent.

Isolated Yields

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SADEGHI et al., Orient. J. Chem., Vol. 31(2), 1175-1179 (2015)

Table 2: Nano Ag/kaolin catalyzed multicomponent synthesis of spirooxindoles (4)
Entry
1
2
3
4
5
6
7
8

1,3-Diketone

Producta

Time min

Yield %b

Ref

Br
Me
NO2
Cl
Br
Me
NO2
Cl

3a
3a
3a
3a
3b
3b
3b
3b

4a
4b
4c
4d
4e
4f
4g
4h

50
45
60
50
60
45
60
60

94
90
87
90
86
88
84
85

26
26
26
26
26
26
26
26

All the products were identified by comparing of melting point and 1H NMR spectra with those of
authentic samples reported in the literature.
b
Yields refer to isolated products.

tetrahydrofuran, acetonitrile, water, dichloromethane,

and ethanol (Table 1, entries 1-5). Of these solvents,
ethanol appears to give the best results. The effects
of temperature were also examined on model reaction.
Decreasing of temperature to 25 C afforded the
product 4a in low yields (Table 1, entry 8). The
dimensions of nano Ag/kaolin were observed with TEM
(Figure 1).

To study the scope of the reaction, a series

of substituted isatins, different cyclic 1,3-diketones and
malononitrile were reacted using nano Ag/kaolin in
refluxing EtOH (Table 2). From the results, it is evident
that all of the reactions provided the desired
spirooxindole products in good to excellent yields
employing both electron-deficient (Table 2, entries 1,
3-5, 7,8) and electron-rich (Table 2, entries 2,6) isatins
as substrates. Though 1,3-cyclohexadione and 5,5-di
methyl-1,3-cyclohexadione gave good results, 5,5-di
methyl-1,3-cyclohexadione gave lower yields and
longer reaction time.
Finally, the recovery and reusability of the
catalyst was investigated in model reaction. After
completion of reaction the mixture was filtered off to
separate the catalyst and then dry the solid residue.
As can be seen from Table 1, the catalyst was
recovered and reused for at least two consecutive
runs without significant loss of activity (Table 1,
entries 6-7).

Fig. 1: TEM image of nano Ag/kaolin

In summary, a mild and efficient method

for the synthesis of spiro-heterocyclic compounds
via one-pot three-component reaction catalyzed by
nano Ag/kaolin is reported. The salient features of
this procedure are high yield, short reaction times,
operational simplicity, and easy separation.

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1179

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